Two phenotypes map to distinct loci on chromosome 4 in lupus-prone NZM2328 mice: high levels of circulating anti-dsDNA antibodies and renal disease. After outcross to the C57L strain, we demonstrated through linkage analysis that levels of circulating antibodies reactive with dsDNA were controlled by locus in the centromeric half of chromosome 4 (Adaz1). The mapping data was confirmed by the generation of a congenic mouse strain bearing protective C57L alleles across this interval. This mouse strain (NZM.Lc4) does not generate high levels of antidsDNA antibodies in serum. However, these mice develop chronic glomerulonephritis associated with immunoglobulin and complement deposits with the same kinetics and prevalence as the parental NZM2328 strain. In another cross, we tested the ability of alleles from another "autoimmune" mouse strain to complement the susceptibility loci of NZM2328 by replacing selected chromosomes of NZM2328 with those from the diabetes prone NOD mouse. Using this consomic strategy, we have shown that NOD chromosome 4 is permissive for high circulating levels of anti-dsDNA antibodies in NZM.Nc4 mice. This demonstrates that NOD alleles at Adaz1 can substitute for NZM alleles to produce this phenotype. However, NZM.Nc4 mice are completely resistant to the development of lupus-like renal disease. This finding shows the presence of a second locus controlling susceptibility to renal disease on chromosome 4 even in the presence of the genomic interval on chromosome 1, which has also shown to be a major susceptibility locus for renal disease in New Zealand mouse lupus models. We will use these congenic and consomic strains to locate the genes responsible for controlling these two traits as the major focus of this project period (Aims 1 and 2). We will determine the mechanism by which Adaz1 controls autoantibody levels in NZM2328 mice (Aim 3). In addition, the possibility of resistance to end-organ damage, responsible for the lack of chronic glomerulonephritis in NZM.Nc4 will be explored (Aim 4) The identification of the second major locus for SLE glomerulonephritis may offer an additional checkpoint for therapeutic intervention in lupus nephritis.